The Experts below are selected from a list of 8075673 Experts worldwide ranked by ideXlab platform
Yuri Kim - One of the best experts on this subject based on the ideXlab platform.
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Retinoic acid receptor β enhanced the anti-cancer stem cells effect of β-carotene by down-regulating expression of Delta-Like 1 homologue in human neuroblastoma cells.
Biochemical and biophysical research communications, 2016Co-Authors: Yoo-sun Kim, Eunju Kim, Yoon Jung Park, Yuri KimAbstract:Neuroblastoma (NB) is childhood malignancy that retains characteristics of cancer stem cells (CSCs). Targeting the CSCs is one of the therapeutic strategies proposed to achieve complete remission of NB. β-carotene (BC), an active precursor of retinoids, is a well-known antioxidant reported to possess anti-CSCs effects. Here, we investigated the involvement of retinoic acid receptors (RARs) in the anti-CSCs effects of BC. Treatment with BC or retinoic acid (RA) upregulated RARβ mRNA expression in two NB cell lines. Inhibition of RARβ using siRNA up-regulated gene expression of Delta-Like 1 homologue (DLK1), a marker of CSCs. To understand the molecular mechanisms of RARβ-mediated inhibition of DLK1, four retinoic acid receptor elements (RAREs) were identified in the promoter of DLK1. Chromatin immunoprecipitation assays indicated that RARβ bound directly to a RARE in the DLK1 promoter region. Knock-down of RARβ also increased the self-renewal capacity of NB cells, which was suppressed by BC. Taken together, this study provided evidence that the therapeutic anti-CSC effects of BC depend on RARβ and its ability to interact with and down-regulate the CSCs marker, DLK1.
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Abstract 3049: Regulation of cancer cell stemness by Delta-Like 1 homolog (Drosophila) and prohibitins
Tumor Biology, 2014Co-Authors: Qun Lin, Asma Begum, Yuri Kim, Zhong YunAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Cancer stem cell characteristics, especially their self-renewal and clonogenic potential, play an essential role in malignant progression and response to anti-cancer therapies. Currently, it remains largely unknown which pathways are involved in the regulation of cancer cell stemness and differentiation. Previously, we found that Delta-Like 1 homolog (Drosophila) or DLK1, a developmentally regulated gene, plays a critical role in regulation of differentiation, self-renewal, and tumorigenic growth of neuroblastoma cells. In order to gain mechanistic understanding of the involvement of DLK1 in intracellular signal transduction, we identified DLK1-interacting proteins using an affinity purification approach. As reported herein, we have found that DLK1 specifically interacts with the prohibitin (PHB) complex via the DLK1 cytoplasmic domain. PHB1 and the closely related PHB2 are encoded by evolutionarily conserved genes and possess diverse functions from mitochondrial structural integrity and oxidative phosphorylation to gene transcription in the nucleus. We have found that DLK1 regulates mitochondrial membrane potential and production of reactive oxygen species (ROS). Our data further reveal a role of PHBs and especially PHB2 in the regulation of cancer cell self-renewal as well as their clonogenic potential. Hence, the DLK1-PHB interaction constitutes a new signaling mechanism that promotes the maintenance of cancer cell stemness. This work was supported by a grant from the National Institutes of Health to ZY (R01CA125021). YK was supported in part by an institutional postdoctoral training grant (T32) from the National Institutes of Health and an Anna Fuller Fund Fellowship from Yale School of Medicine. Citation Format: Qun Lin, Asma Begum, Chenye Yu, Ming-Yeah Hu, Yuri Kim, Zhong Yun. Regulation of cancer cell stemness by Delta-Like 1 homolog (Drosophila) and prohibitins. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3049. doi:10.1158/1538-7445.AM2014-3049
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Interaction of Delta-Like 1 Homolog (Drosophila) with Prohibitins and Its Impact on Tumor Cell Clonogenicity
Molecular cancer research : MCR, 2013Co-Authors: Asma Begum, Yuri Kim, Qun Lin, Zhong YunAbstract:Cancer stem cell characteristics, especially their self-renewal and clonogenic potentials, play an essential role in malignant progression and response to anticancer therapies. Currently, it remains largely unknown what pathways are involved in the regulation of cancer cell stemness and differentiation. Previously, we found that Delta-Like 1 homolog (Drosophila) or DLK1, a developmentally regulated gene, plays a critical role in the regulation of differentiation,self-renewal,andtumorigenicgrowthofneuroblastomacells.Here,weshowthatDLK1specifically interacts with the prohibitin 1 (PHB1) and PHB2, two closely related genes with pleiotropic functions, including regulationofmitochondrialfunctionandgenetranscription.DLK1interactswiththePHB1–PHB2complexviaits cytoplasmic domain and regulates mitochondrial functions, including mitochondrial membrane potential and production of reactive oxygen species. We have further found that PHB1 and especially PHB2 regulate cancer cell self-renewal as well as their clonogenic potential. Hence, the DLK1–PHB interaction constitutes a new signaling pathway that maintains clonogenicity and self-renewal potential of cancer cells.
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Abstract 4383: Regulation of cancer cell differentiation in vivo by Delta-Like 1 homolog (Drosophila) DLK1
Tumor Biology, 2011Co-Authors: Asma Begum, Yuri Kim, Qun Lin, Zhong YunAbstract:Malignant tumor progression from a benign growth to metastasis is often accompanied by an accumulation of multiple genetic and epigenetic changes occurring over a course of more than a decade. The stem cell-like characteristics, especially the self-renewal capacity, of tumor cells is essential for uninterrupted inheritance of these disparate genetic and epigenetic changes in the same originating tumor cell. Like normal stem cells, cancer cells can lose their stemness or self-renewal potential in response to environmental stresses. Therefore, tumor cell stemness needs to be actively maintained. However, the underlying mechanisms remain to be clearly understood. Our previous studies and others have suggested that the tumor microenvironment, including hypoxia, plays a significant role in the regulation of cancer stem cell characteristics. We have identified a previously uncharacterized stem cell pathway mediated by DLK1 or Delta-Like 1 homolog (Drosophila) that is upregulated by hypoxia and enhances cancer cell stemness and tumorigenicity in neuronal tumors. In this study, we investigated the role of DLK1 in the regulation of cancer cell differentiation in vivo using neuroblastoma (NB) xenografts as a model. Our findings have revealed that overexpression of DLK1 promotes tumor growth by increasing the number of mitotic or proliferative cells and inducing angiogenesis. On the other hand, tumors derived from NB cells with down regulation of DLK1 expression by RNA interference or with overexpression of dominant negative mutants of DLK1 sensitize NB cells to undergo differentiation, as shown by increased expression of neuronal and glial differentiation markers. These results demonstrate that DLK1 plays an important role in the maintenance of undifferentiated, stem cell-like phenotype of NB cells in vivo. Our findings also indicate that the tumor microenvironment, especially hypoxia, can exert a profound impact on the tumor cell fate in vivo by regulating specific stem cell pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2011-4383
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The effects of nutrient depleted microenvironments and Delta-Like 1 homologue (DLK1) on apoptosis in neuroblastoma.
Nutrition research and practice, 2010Co-Authors: Yuri KimAbstract:The tumor microenvironment, particularly sufficient nutrition and oxygen supply, is important for tumor cell survival. Nutrition deprivation causes cancer cell death. Since apoptosis is a major mechanism of neuronal loss, we explored neuronal apoptosis in various microenvironment conditions employing neuroblastoma (NB) cells. To investigate the effects of tumor malignancy and differentiation on apoptosis, the cells were exposed to poor microenvironments characterized as serum-free, low-glucose, and hypoxia. Incubation of the cells in serum-free and low-glucose environments significantly increased apoptosis in less malignant and more differentiated N-type IMR32 cells, whereas more malignant and less differentiated I-type BE(2)C cells were not affected by those treatments. In contrast, hypoxia (1% O2) did not affect apoptosis despite cell malignancy. It is suggested that DLK1 constitutes an important stem cell pathway for regulating self-renewal, clonogenicity, and tumorigenicity. This raises questions about the role of DLK1 in the cellular resistance of cancer cells under poor microenvironments, which cancer cells normally encounter. In the present study, DLK1 overexpression resulted in marked protection from apoptosis induced by nutrient deprivation. This in vitro model demonstrated that increasing severity of nutrition deprivation and knock-down of DLK1 caused greater apoptotic death, which could be a useful strategy for targeted therapies in fighting NB as well as for evaluating how nutrient deprived cells respond to therapeutic manipulation.
Charlotte Harken Jensen - One of the best experts on this subject based on the ideXlab platform.
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The non-canonical NOTCH1 ligand Delta-Like 1 homolog (DLK1) self interacts in mammals
International Journal of Biological Macromolecules, 2017Co-Authors: Gunnhildur Asta Traustadottir, Søren P. Sheikh, Charlotte Harken Jensen, Jose Javier Garcia Ramirez, Hans Christian Beck, Ditte Caroline AndersenAbstract:Abstract Delta-Like 1 homolog (DLK1) is an imprinted gene, which is widely expressed during mammalian development and plays a pivotal role in differentiation of various tissue types. Most recently, we have shown that DLK1 interacts with NOTCH1, yet several Notch independent mechanisms have previously been suggested as well, but only poorly confirmed in a mammalian context. In the present study, we employed the mammalian two-hybrid (MTH) system, a genetic in vivo protein–protein interaction system, to show robust DLK1-DLK1, DLK1-FnI (Fibronectin) and DLK1-CFR (cysteine-rich FGF receptor) interactions, whereas the proposed DLK1-IGFBP1 interaction was not supported by MTH. Very little has previously been described on the DLK1 self-interaction. Herein, we showed by immunoprecipitation as well as Sulfo-SBED label transfer that the DLK1-DLK1 interaction likely is part of Dlk1’s function in preadipocytes. Furthermore our data suggest that DLK1 interacts with itself through EGF domain 4 and 5, which is distinct from the recently described NOTCH1-DLK1 interaction, which occurs between EGF domain 5 and 6. This opens up the possibility that Notch independent mechanisms like the DLK1-DLK1 interaction may modulate the non-canonical NOTCH1-DLK1 interaction further complexing this system.
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evidence of non canonical notch signaling delta like 1 homolog dlk1 directly interacts with the notch1 receptor in mammals
Cellular Signalling, 2016Co-Authors: Gunnhildur Asta Traustadottir, Søren P. Sheikh, Charlotte Harken Jensen, Sussi B Mortensen, Hans Christian Beck, Mads Thomassen, Victoriano Baladron, Jorge Laborda, Ditte Caroline AndersenAbstract:Abstract Canonical NOTCH signaling, known to be essential for tissue development, requires the Delta-Serrate-LAG2 (DSL) domain for NOTCH to interact with its ligand. However, despite lacking DSL, Delta-Like 1 homolog (DLK1), a protein that plays a significant role in mammalian development, has been suggested to interact with NOTCH1 and act as an antagonist. This non-canonical interaction is, however controversial, and evidence for a direct interaction, still lacking in mammals. In this study, we elucidated the putative DLK1-NOTCH1 interaction in a mammalian context. Taking a global approach and using Dlk1+/+ and Dlk1−/− mouse tissues at E16.5, we demonstrated that several NOTCH signaling pathways indeed are affected by DLK1 during tissue development, and this was supported by a lower activation of NOTCH1 protein in Dlk1+/+ embryos. Likewise, but using a distinct Dlk1-manipulated (siRNA) setup in a mammalian cell line, NOTCH signaling was substantially inhibited by DLK1. Using a mammalian two-hybrid system, we firmly established that the effect of DLK1 on NOTCH signaling was due to a direct interaction between DLK1 and NOTCH1. By careful dissection of this mechanism, we found this interaction to occur between EGF domains 5 and 6 of DLK1 and EGF domains 10–15 of NOTCH1. Thus, our data provide the first evidence for a direct interaction between DLK1 and NOTCH1 in mammals, and substantiate that non-canonical NOTCH ligands exist, adding to the complexity of NOTCH signaling.
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characterization of fetal antigen 1 delta like 1 homologue expressing cells in the rat nigrostriatal system effects of a unilateral 6 hydroxydopamine lesion
PLOS ONE, 2015Co-Authors: Remy Liechti, Charlotte Harken Jensen, Angelique Ducray, Pia Jensen, Stefano Di Santo, Stefanie Seiler, Morten Meyer, Hans Rudolf WidmerAbstract:Fetal antigen 1/Delta-Like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes.
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dual role of delta like 1 homolog dlk1 in skeletal muscle development and adult muscle regeneration
Development, 2013Co-Authors: Søren P. Sheikh, Ditte Caroline Andersen, Victoriano Baladron, Jorge Laborda, Moustapha Kassem, Charlotte Harken JensenAbstract:Muscle development and regeneration is tightly orchestrated by a specific set of myogenic transcription factors. However, factors that regulate these essential myogenic inducers remain poorly described. Here, we show that Delta-Like 1 homolog ( Dlk1 ), an imprinted gene best known for its ability to inhibit adipogenesis, is a crucial regulator of the myogenic program in skeletal muscle. Dlk1 -/- mice were developmentally retarded in their muscle mass and function owing to inhibition of the myogenic program during embryogenesis. Surprisingly however, Dlk1 depletion improves in vitro and in vivo adult skeletal muscle regeneration by substantial enhancement of the myogenic program and muscle function, possibly by means of an increased number of available myogenic precursor cells. By contrast, Dlk1 fails to alter the adipogenic commitment of muscle-derived progenitors in vitro , as well as intramuscular fat deposition during in vivo regeneration. Collectively, our results suggest a novel and surprising dual biological function of DLK1 as an enhancer of muscle development, but as an inhibitor of adult muscle regeneration.
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Preadipocytes proliferate and differentiate under the guidance of Delta-Like 1 homolog (DLK1).
Adipocyte, 2013Co-Authors: Gunnhildur Asta Traustadottir, Søren P. Sheikh, Charlotte Harken Jensen, Rok Kosmina, Ditte Caroline AndersenAbstract:Obesity occurs when an excessive dietary fat intake leads to expansion of adipose tissue, which mainly consists of adipocytes that arise from proliferating and differentiating adipose stem cells, the preadipocytes. Obesity is a consequence of both adipocyte hypertrophy and hyperplasia. Knowledge about preadipocyte differentiation is relatively well established, whereas the mechanism responsible for preadipocyte proliferation is incompletely understood and only in the early stage of comprehension. In this regard, we have recently identified that Delta-Like 1 homolog (Dlk1) (also known as Preadipocyte factor 1 [Pref-1]) inhibits preadipocyte proliferation by regulating their entry into G1/S-phase. This novel disclosure, adding to the previous published data on Dlk1 repression of preadipocyte differentiation, has given us the chance to firmly place Dlk1 as a master regulator of preadipocyte homeostasis and adipose tissue expansion. Dlk1 manipulation may, therefore, open new perspectives in obesity treatments.
Zhong Yun - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3049: Regulation of cancer cell stemness by Delta-Like 1 homolog (Drosophila) and prohibitins
Tumor Biology, 2014Co-Authors: Qun Lin, Asma Begum, Yuri Kim, Zhong YunAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Cancer stem cell characteristics, especially their self-renewal and clonogenic potential, play an essential role in malignant progression and response to anti-cancer therapies. Currently, it remains largely unknown which pathways are involved in the regulation of cancer cell stemness and differentiation. Previously, we found that Delta-Like 1 homolog (Drosophila) or DLK1, a developmentally regulated gene, plays a critical role in regulation of differentiation, self-renewal, and tumorigenic growth of neuroblastoma cells. In order to gain mechanistic understanding of the involvement of DLK1 in intracellular signal transduction, we identified DLK1-interacting proteins using an affinity purification approach. As reported herein, we have found that DLK1 specifically interacts with the prohibitin (PHB) complex via the DLK1 cytoplasmic domain. PHB1 and the closely related PHB2 are encoded by evolutionarily conserved genes and possess diverse functions from mitochondrial structural integrity and oxidative phosphorylation to gene transcription in the nucleus. We have found that DLK1 regulates mitochondrial membrane potential and production of reactive oxygen species (ROS). Our data further reveal a role of PHBs and especially PHB2 in the regulation of cancer cell self-renewal as well as their clonogenic potential. Hence, the DLK1-PHB interaction constitutes a new signaling mechanism that promotes the maintenance of cancer cell stemness. This work was supported by a grant from the National Institutes of Health to ZY (R01CA125021). YK was supported in part by an institutional postdoctoral training grant (T32) from the National Institutes of Health and an Anna Fuller Fund Fellowship from Yale School of Medicine. Citation Format: Qun Lin, Asma Begum, Chenye Yu, Ming-Yeah Hu, Yuri Kim, Zhong Yun. Regulation of cancer cell stemness by Delta-Like 1 homolog (Drosophila) and prohibitins. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3049. doi:10.1158/1538-7445.AM2014-3049
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Interaction of Delta-Like 1 Homolog (Drosophila) with Prohibitins and Its Impact on Tumor Cell Clonogenicity
Molecular cancer research : MCR, 2013Co-Authors: Asma Begum, Yuri Kim, Qun Lin, Zhong YunAbstract:Cancer stem cell characteristics, especially their self-renewal and clonogenic potentials, play an essential role in malignant progression and response to anticancer therapies. Currently, it remains largely unknown what pathways are involved in the regulation of cancer cell stemness and differentiation. Previously, we found that Delta-Like 1 homolog (Drosophila) or DLK1, a developmentally regulated gene, plays a critical role in the regulation of differentiation,self-renewal,andtumorigenicgrowthofneuroblastomacells.Here,weshowthatDLK1specifically interacts with the prohibitin 1 (PHB1) and PHB2, two closely related genes with pleiotropic functions, including regulationofmitochondrialfunctionandgenetranscription.DLK1interactswiththePHB1–PHB2complexviaits cytoplasmic domain and regulates mitochondrial functions, including mitochondrial membrane potential and production of reactive oxygen species. We have further found that PHB1 and especially PHB2 regulate cancer cell self-renewal as well as their clonogenic potential. Hence, the DLK1–PHB interaction constitutes a new signaling pathway that maintains clonogenicity and self-renewal potential of cancer cells.
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Abstract 4383: Regulation of cancer cell differentiation in vivo by Delta-Like 1 homolog (Drosophila) DLK1
Tumor Biology, 2011Co-Authors: Asma Begum, Yuri Kim, Qun Lin, Zhong YunAbstract:Malignant tumor progression from a benign growth to metastasis is often accompanied by an accumulation of multiple genetic and epigenetic changes occurring over a course of more than a decade. The stem cell-like characteristics, especially the self-renewal capacity, of tumor cells is essential for uninterrupted inheritance of these disparate genetic and epigenetic changes in the same originating tumor cell. Like normal stem cells, cancer cells can lose their stemness or self-renewal potential in response to environmental stresses. Therefore, tumor cell stemness needs to be actively maintained. However, the underlying mechanisms remain to be clearly understood. Our previous studies and others have suggested that the tumor microenvironment, including hypoxia, plays a significant role in the regulation of cancer stem cell characteristics. We have identified a previously uncharacterized stem cell pathway mediated by DLK1 or Delta-Like 1 homolog (Drosophila) that is upregulated by hypoxia and enhances cancer cell stemness and tumorigenicity in neuronal tumors. In this study, we investigated the role of DLK1 in the regulation of cancer cell differentiation in vivo using neuroblastoma (NB) xenografts as a model. Our findings have revealed that overexpression of DLK1 promotes tumor growth by increasing the number of mitotic or proliferative cells and inducing angiogenesis. On the other hand, tumors derived from NB cells with down regulation of DLK1 expression by RNA interference or with overexpression of dominant negative mutants of DLK1 sensitize NB cells to undergo differentiation, as shown by increased expression of neuronal and glial differentiation markers. These results demonstrate that DLK1 plays an important role in the maintenance of undifferentiated, stem cell-like phenotype of NB cells in vivo. Our findings also indicate that the tumor microenvironment, especially hypoxia, can exert a profound impact on the tumor cell fate in vivo by regulating specific stem cell pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2011-4383
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Abstract 464: Hypoxia-regulated Delta-Like 1 homologue (DLK1) enhances cancer cell stemness and tumorigenicity
Tumor Biology, 2010Co-Authors: Yuri Kim, Qun Lin, Daniel Zelterman, Zhong YunAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Tumor hypoxia, i.e. O2 deficiency, is a common feature of solid tumors and predicts poor clinical outcomes. Tumor hypoxia is associated with increased aggressiveness and resistance to cancer therapies. Hypoxic tumors appear to be poorly differentiated and express stem/progenitor cell genes. It remains unclear, however, whether and how hypoxia regulates cancer cell differentiation and maintains cancer cell stemness. In this study, we demonstrate that hypoxia increases the expression of Delta-Like 1 homolog (DLK1), a transmembrane protein mainly expressed in stem/progenitor cells. Both HIF-1α and HIF-2α can bind to the DLK1 promoter. Using neuroblastoma (NB) cells as a model, we have found that DLK1 is highly expressed in undifferentiated, but not in differentiated, NB tumor cells. Downregulation of DLK1 expression by siRNA interference results in spontaneous differentiation, whereas overexpression of DLK1 inhibits retinoic acid-induced differentiation. We have further found that DLK1 is required for maintaining tumor sphere growth, a key feature reflecting the cancer stem cell-like characteristics. Importantly, we have demonstrated that loss of DLK1 expression leads to significantly reduced clonogenic growth in vitro, suppressed tumor take and growth of tumor xenografts in vivo. Furthermore, we have found that the intracellular domain of DLK1, especially its two conserved putative phosphorylation sites (Tyrosine 339 and Serine 355), is required for its biological functions. In summary, our results clearly demonstrate that DLK1 has the ability to regulate all the key aspects of cancer stem cell-like characteristics, i.e. tumor cell differentiation, self-renewal (tumor sphere growth), clonogenicity, and tumorigenicity. Because elevated DLK1 expression is also found in many tumor types, our observations suggest that hypoxia and DLK1 may constitute an important stem cell pathway for the regulation of cancer stem cell-like functionality and tumorigenicity by the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 464.
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hypoxia regulated delta like 1 homologue enhances cancer cell stemness and tumorigenicity
Cancer Research, 2009Co-Authors: Yuri Kim, Qun Lin, Daniel Zelterman, Zhong YunAbstract:Reduced oxygenation, or hypoxia, inhibits differentiation and facilitates stem cell maintenance. Hypoxia commonly occurs in solid tumors and promotes malignant progression. Hypoxic tumors are aggressive and exhibit stem cell–like characteristics. It remains unclear, however, whether and how hypoxia regulates cancer cell differentiation and maintains cancer cell stemness. Here, we show that hypoxia increases the expression of the stem cell gene DLK1 , or Delta-Like 1 homologue ( Drosophila ), in neuronal tumor cells. Inhibition of DLK1 enhances spontaneous differentiation, decreases clonogenicity, and reduces in vivo tumor growth. Overexpression of DLK1 inhibits differentiation and enhances tumorigenic potentials. We further show that the DLK1 cytoplasmic domain, especially Tyrosine339 and Serine355, is required for maintaining both clonogenicity and tumorigenicity. Because elevated DLK1 expression is found in many tumor types, our observations suggest that hypoxia and DLK1 may constitute an important stem cell pathway for the regulation of cancer stem cell–like functionality and tumorigenicity. [Cancer Res 2009;69(24):9271–80]
Ditte Caroline Andersen - One of the best experts on this subject based on the ideXlab platform.
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The non-canonical NOTCH1 ligand Delta-Like 1 homolog (DLK1) self interacts in mammals
International Journal of Biological Macromolecules, 2017Co-Authors: Gunnhildur Asta Traustadottir, Søren P. Sheikh, Charlotte Harken Jensen, Jose Javier Garcia Ramirez, Hans Christian Beck, Ditte Caroline AndersenAbstract:Abstract Delta-Like 1 homolog (DLK1) is an imprinted gene, which is widely expressed during mammalian development and plays a pivotal role in differentiation of various tissue types. Most recently, we have shown that DLK1 interacts with NOTCH1, yet several Notch independent mechanisms have previously been suggested as well, but only poorly confirmed in a mammalian context. In the present study, we employed the mammalian two-hybrid (MTH) system, a genetic in vivo protein–protein interaction system, to show robust DLK1-DLK1, DLK1-FnI (Fibronectin) and DLK1-CFR (cysteine-rich FGF receptor) interactions, whereas the proposed DLK1-IGFBP1 interaction was not supported by MTH. Very little has previously been described on the DLK1 self-interaction. Herein, we showed by immunoprecipitation as well as Sulfo-SBED label transfer that the DLK1-DLK1 interaction likely is part of Dlk1’s function in preadipocytes. Furthermore our data suggest that DLK1 interacts with itself through EGF domain 4 and 5, which is distinct from the recently described NOTCH1-DLK1 interaction, which occurs between EGF domain 5 and 6. This opens up the possibility that Notch independent mechanisms like the DLK1-DLK1 interaction may modulate the non-canonical NOTCH1-DLK1 interaction further complexing this system.
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evidence of non canonical notch signaling delta like 1 homolog dlk1 directly interacts with the notch1 receptor in mammals
Cellular Signalling, 2016Co-Authors: Gunnhildur Asta Traustadottir, Søren P. Sheikh, Charlotte Harken Jensen, Sussi B Mortensen, Hans Christian Beck, Mads Thomassen, Victoriano Baladron, Jorge Laborda, Ditte Caroline AndersenAbstract:Abstract Canonical NOTCH signaling, known to be essential for tissue development, requires the Delta-Serrate-LAG2 (DSL) domain for NOTCH to interact with its ligand. However, despite lacking DSL, Delta-Like 1 homolog (DLK1), a protein that plays a significant role in mammalian development, has been suggested to interact with NOTCH1 and act as an antagonist. This non-canonical interaction is, however controversial, and evidence for a direct interaction, still lacking in mammals. In this study, we elucidated the putative DLK1-NOTCH1 interaction in a mammalian context. Taking a global approach and using Dlk1+/+ and Dlk1−/− mouse tissues at E16.5, we demonstrated that several NOTCH signaling pathways indeed are affected by DLK1 during tissue development, and this was supported by a lower activation of NOTCH1 protein in Dlk1+/+ embryos. Likewise, but using a distinct Dlk1-manipulated (siRNA) setup in a mammalian cell line, NOTCH signaling was substantially inhibited by DLK1. Using a mammalian two-hybrid system, we firmly established that the effect of DLK1 on NOTCH signaling was due to a direct interaction between DLK1 and NOTCH1. By careful dissection of this mechanism, we found this interaction to occur between EGF domains 5 and 6 of DLK1 and EGF domains 10–15 of NOTCH1. Thus, our data provide the first evidence for a direct interaction between DLK1 and NOTCH1 in mammals, and substantiate that non-canonical NOTCH ligands exist, adding to the complexity of NOTCH signaling.
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dual role of delta like 1 homolog dlk1 in skeletal muscle development and adult muscle regeneration
Development, 2013Co-Authors: Søren P. Sheikh, Ditte Caroline Andersen, Victoriano Baladron, Jorge Laborda, Moustapha Kassem, Charlotte Harken JensenAbstract:Muscle development and regeneration is tightly orchestrated by a specific set of myogenic transcription factors. However, factors that regulate these essential myogenic inducers remain poorly described. Here, we show that Delta-Like 1 homolog ( Dlk1 ), an imprinted gene best known for its ability to inhibit adipogenesis, is a crucial regulator of the myogenic program in skeletal muscle. Dlk1 -/- mice were developmentally retarded in their muscle mass and function owing to inhibition of the myogenic program during embryogenesis. Surprisingly however, Dlk1 depletion improves in vitro and in vivo adult skeletal muscle regeneration by substantial enhancement of the myogenic program and muscle function, possibly by means of an increased number of available myogenic precursor cells. By contrast, Dlk1 fails to alter the adipogenic commitment of muscle-derived progenitors in vitro , as well as intramuscular fat deposition during in vivo regeneration. Collectively, our results suggest a novel and surprising dual biological function of DLK1 as an enhancer of muscle development, but as an inhibitor of adult muscle regeneration.
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Preadipocytes proliferate and differentiate under the guidance of Delta-Like 1 homolog (DLK1).
Adipocyte, 2013Co-Authors: Gunnhildur Asta Traustadottir, Søren P. Sheikh, Charlotte Harken Jensen, Rok Kosmina, Ditte Caroline AndersenAbstract:Obesity occurs when an excessive dietary fat intake leads to expansion of adipose tissue, which mainly consists of adipocytes that arise from proliferating and differentiating adipose stem cells, the preadipocytes. Obesity is a consequence of both adipocyte hypertrophy and hyperplasia. Knowledge about preadipocyte differentiation is relatively well established, whereas the mechanism responsible for preadipocyte proliferation is incompletely understood and only in the early stage of comprehension. In this regard, we have recently identified that Delta-Like 1 homolog (Dlk1) (also known as Preadipocyte factor 1 [Pref-1]) inhibits preadipocyte proliferation by regulating their entry into G1/S-phase. This novel disclosure, adding to the previous published data on Dlk1 repression of preadipocyte differentiation, has given us the chance to firmly place Dlk1 as a master regulator of preadipocyte homeostasis and adipose tissue expansion. Dlk1 manipulation may, therefore, open new perspectives in obesity treatments.
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membrane tethered delta like 1 homolog dlk1 restricts adipose tissue size by inhibiting preadipocyte proliferation
Diabetes, 2012Co-Authors: Sussi B Mortensen, Søren P. Sheikh, Charlotte Harken Jensen, Mikael Schneider, Mads Thomassen, Torben A. Kruse, Jorge Laborda, Ditte Caroline AndersenAbstract:Adipocyte renewal from preadipocytes has been shown to occur throughout life and to contribute to obesity, yet very little is known about the molecular circuits that control preadipocyte expansion. The soluble form of the preadipocyte factor (also known as pref-1) Delta-Like 1 homolog (DLK1S) is known to inhibit adipogenic differentiation; however, the impact of DLK1 isoforms on preadipocyte proliferation remains to be determined. We generated preadipocytes with different levels of DLK1 and examined differentially affected gene pathways, which were functionally tested in vitro and confirmed in vivo. Here, we demonstrate for the first time that only membrane-bound DLK1 (DLK1M) exhibits a substantial repression effect on preadipocyte proliferation. Thus, by independently manipulating DLK1 isoform levels, we established that DLK1M inhibits G1-to-S-phase cell cycle progression and thereby strongly inhibits preadipocyte proliferation in vitro. Adult DLK1-null mice exhibit higher fat amounts than wild-type controls, and our in vivo analysis demonstrates that this may be explained by a marked increase in preadipocyte replication. Together, these data imply a major dual inhibitory function of DLK1 on adipogenesis, which places DLK1 as a master regulator of preadipocyte homeostasis, suggesting that DLK1 manipulation may open new avenues in obesity treatment.
Anna Zolkiewska - One of the best experts on this subject based on the ideXlab platform.
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the role of delta like 1 shedding in muscle cell self renewal and differentiation
Development, 2008Co-Authors: Danqiong Sun, Anna ZolkiewskaAbstract:1. 1. Sun D., 2. et al. 2008. J. Cell Sci. doi:10.1242/jcs.035493 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft.jtitle%253DJ.%2BCell%2BSci.%26rft_id%253Dinfo%253Adoi%252F10.1242%252Fjcs.035493%26rft_id%253Dinfo%253Apmid%252F18957511%26rft.genre%
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the role of delta like 1 shedding in muscle cell self renewal and differentiation
Journal of Cell Science, 2008Co-Authors: Danqiong Sun, Anna ZolkiewskaAbstract:Myogenic cells have the ability to adopt two divergent fates upon exit from the cell cycle: differentiation or self-renewal. The Notch signaling pathway is a well-known negative regulator of myogenic differentiation. Using mouse primary myoblasts cultured in vitro or C2C12 myogenic cells, we found that Notch activity is essential for maintaining the expression of Pax7, a transcription factor associated with the self-renewal lineage, in quiescent undifferentiated myoblasts after they exit the cell cycle. Stimulation of the Notch pathway by expression of a constitutively active Notch-1, or co-culture of myogenic cells with CHO cells transfected with Delta like-1 (DLL1), increases the level of Pax7. DLL1, a ligand for Notch receptor, is shed by ADAM metalloproteases in a pool of Pax7 + C2C12 reserve cells, but it remains intact in differentiated myotubes. DLL1 shedding changes the receptor/ligand ratio and modulates the level of Notch signaling. Inhibition of DLL1 cleavage by a soluble, dominant-negative mutant form of ADAM12 leads to elevation of Notch signaling, inhibition of differentiation, and expansion of the pool of self-renewing Pax7 + /MyoD – cells. These results suggest that ADAM-mediated shedding of DLL1 in a subset of cells during myogenic differentiation in vitro contributes to downregulation of Notch signaling in neighboring cells and facilitates their progression into differentiation. We propose that the proteolytic processing of DLL1 helps achieve an asymmetry in Notch signaling in initially equivalent myogenic cells and helps sustain the balance between differentiation and self-renewal.
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PROTEOLYTIC PROCESSING OF Delta-Like 1 BY ADAM PROTEASES
Journal of Biological Chemistry, 2006Co-Authors: Emilia Dyczynska, Atsuko Sehara-fujisawa, Carl P. Blobel, Haiqing Yi, Anna ZolkiewskaAbstract:Abstract Delta-Like 1 (Dll1) is a mammalian ligand for Notch receptors. Interactions between Dll1 and Notch in trans activate the Notch pathway, whereas Dll1 binding to Notch in cis inhibits Notch signaling. Dll1 undergoes proteolytic processing in its extracellular domain by ADAM10. In this work we demonstrate that Dll1 represents a substrate for several other members of the ADAM family. In co-transfected cells, Dll1 is constitutively cleaved by ADAM12, and the N-terminal fragment of Dll1 is released to medium. ADAM12-mediated cleavage of Dll1 is cell density-dependent, takes place in cis orientation, and does not require the presence of the cytoplasmic domain of ADAM12. Full-length Dll1, but not its N- or C-terminal proteolytic fragment, co-immunoprecipitates with ADAM12. By using a Notch reporter construct, we show that Dll1 processing by ADAM12 increases Notch signaling in a cell-autonomous manner. Furthermore, ADAM9 and ADAM17 have the ability to process Dll1. In contrast, ADAM15 does not cleave Dll1, although the two proteins still co-immunoprecipitate with each other. Asn-353 present in the catalytic motif of ADAM12 and other Dll1-processing ADAMs, but absent in ADAM15, is necessary for Dll1 cleavage. Dll1 cleavage is reduced in ADAM9/12/15-/- mouse embryonic fibroblasts (MEFs), suggesting that the endogenous ADAM9 and/or ADAM12 present in wild type MEFs contribute to Dll1 processing. Finally, the endogenous Dll1 present in primary mouse myoblasts undergoes cleavage in confluent, differentiating myoblast cultures, and this cleavage is decreased by ADAM12 small interfering RNAs. Our findings expand the role of ADAM proteins in the regulation of Notch signaling.